4.1.1. Garlic

It was observed that garlic reduces total cholesterol by almost 5% and LDL-C by 6% in subjects with elevated total cholesterol levels (mean TC > 200 mg/dL), and has a statistically non-significant effect on HDL-C and triglycerides. This observed reduction in LDL and total cholesterol is clinically relevant as it is associated with a reduction in the risk of adverse coronary and vascular events [69,70].

The results also suggested that garlic was highly tolerable and does not pose any side effects, which are more common with conventional therapies. In a majority of the studies, bad smell or odor was the only major side effect of garlic. A small proportion of the population did experience some gastrointestinal issues such as belching and acid reflux, but in comparison to statins, these side effects are not serious. Statins, on the other hand, do pose some serious adverse effects including a high risk of diabetes, cognitive and muscular impairment, sexual dysfunction, mood swings, anxiety, and irritability [73].

These findings corroborate the results of previous meta-analyses and systematic reviews [74–76]. In previous literature, the effect of garlic on cholesterol levels has been a debatable topic. Time and again, many individual trials of garlic have reported diverse therapeutic effect size of garlic on cholesterol levels. The study by Stevinson et al. [76] was one of the earliest meta-analysis of garlic on hypercholesterolemia and included 13 trials, whereas the recent and most updated study, by Ried et al. [74], included 39 studies. The studies by Stevinson et al. and Ried et al. both sugges<sup>t</sup> that garlic reduces TC levels by approximately 15 mg/dL, whereas the study by Reinhart et al. [75] suggests its effect size is nearly half of what was observed by previous studies, i.e., −7.34 mg/dL. They attribute this smaller effect size to including newer studies, which exhibit more modest effects than older studies. However, the recent and most updated meta-analysis on garlic by Ried et al. [74] seems to be the most comprehensive one.

Meanwhile, observed results from this study have suggested that garlic has a modest effect size of −12.45 mg/dL. One reason behind this finding may have to do with the type of included studies in this review. Because Ayurveda does not entertain the use of aged garlic, extracted garlic oil, or extracted compound of allicin from garlic, and uses whole garlic as a preparation, this work did not include any of the studies that used those various forms of garlic as an intervention. There is a common trend of using aged garlic and a lot of studies had to be excluded for using aged garlic as an intervention. However, the studies that used whole garlic or dried garlic powder were included, as it is the common practice to use whole garlic cloves in Ayurvedic pharmaceutical science [71]. From a pharmacological point of view, it is believed that the active compound called allicin, a garlic derivative, is responsible for reducing cholesterol levels and for the distinctive smell of garlic [77]. Allicin is a volatile compound and is responsible transiently for cardiovascular effects [77]. However, the exact ingredients and their mechanism of action still remains unknown. On the other hand, Ayurveda has been using garlic for treating Hridroga, an Ayurvedic term for cardiovascular diseases [71]. In Ayurveda, garlic, which possesses all five tastes except sour taste, is capable for clearing channels and all the coverings (avarana) because of its pungen<sup>t</sup> and piercing qualities [71,78].

In conclusion, the findings of this review sugges<sup>t</sup> that garlic is superior to placebos in reducing elevated total cholesterol and LDL-C levels. Garlic has also been shown to have additional cardiovascular benefits such as reducing high blood pressure [79]. When taken together, garlic preparations can be considered as a general heart tonic with cholesterol regulating properties. It can also be used as a preventive agen<sup>t</sup> in borderline cholesterol levels, with a higher safety and tolerability profile than statins.

#### 4.1.2. Nigella Sativa

Another intervention that showed some efficacy on cholesterol levels was *Nigella sativa*. Commonly known as black cumin and Upakunchika in Ayurveda, it is more famous for its digestive effect. Ideally, *Nigella sativa* seed powder is used in Ayurveda, so studies of its seed oil or other extracts were not included. Based on the analysis of three studies on *Nigella sativa*, it was observed that it reduces total cholesterol by 9.28 mg/dL (95% C.I.: 17.36 to 1.19, *p* = 0.02). However, it does not seem to have a statistically significant effect on other parameters such as LDL-C 2.12 mg/dL (95% C.I.: 7.85 to 3.6; *p* = 0.47), triglycerides 21.09 mg/dL (95% C.I.: to −2.77; *p* = 0.08), and HDL-C 1.92 mg/dL (95% C.I.:1.62 to 5.45; *p* = 0.29). This observation is comparable to the results of a recently published systematic review by Sahebkar et al. [80]. The difference between the current study and [80] is the inclusion criteria; the present study only included studies with whole seed powder, whereas Sahebkar et al. [80] included other versions of *Nigella sativa* such as seed oil and also had no restriction on baseline total cholesterol levels for the inclusion criteria, which limited the number of studies in this meta-analysis.

As an addition to the herbs mentioned above, we also conducted a systematic review to examine the effects of *Terminalia arjuna* on lipid parameters of hypercholesterolemic patients. Due to a lack of strict randomized controlled designs and inconsistencies in Arjuna preparations being used, the meta-analytic results are not included in our main results section. Nonetheless, the findings from such quasi-randomized studies are still worth mentioning. After analyzing data from 14 arms of 10 different studies enrolling 547 participants, it was observed that Ayurvedic herbal preparations with *Terminalia arjuna* as a main ingredient reduces total cholesterol by 19.47 mg/dL (95% C.I.:30.73, 8.20, *p* = 0.0007), LDL-C by 16.33 mg/dL (95% C.I.:23.21, 9.45, *p* < 0.00001), triglycerides by 11.24 mg/dL (95% C.I.:22.02, 0.46, *p* = 0.04), and raises HDL-C by 5.16 mg/dL (95% C.I.:2.62, 7.69, *p* < 0.00001). Overall, Arjuna may also be considered as a viable herb that can be quite beneficial for patients with hypercholesterolemia.

#### 4.1.3. Adverse Effects

No serious adverse events were reported in the majority of the studies, except Szapary (2003) [21] reported that one patient each from experimental group and control group had serious side effects and Joseph (2012) reported that one participant in the active control group withdrew due to a five-fold increase in serum creatinine level. Other minor adverse events such as gastrointestinal upset, skin rashes, nausea, and bad odor of breath and body were also reported in few other studies [47,56].

Limitations: Although every effort was made to discover all eligible studies published through December 2020, there is a possibility of some studies still being left behind. Most of the studies that were seemingly eligible did not qualify given our inclusion criteria, but some of the studies did show consistent findings with our study [55–57]. A Pakistani study by Zeb et al. [81] examined the impact of garlic powder, coriander powder, and a mixture of the two on lipid profile as compared to a placebo. Garlic powder was found to be the most effective in reducing TC and LDL and increasing HDL, as compared to all other groups. The latest study by Iskander et al. [82] showed that a nutraceutical combination including g gugguluipid showed a significant reduction in TC and LDL levels after 8 weeks of consumption in a randomized, placebo-controlled double-blind trial. Another study by Kuchewar et al. [83] found beneficial effects of Triphala on the lipid profile of patients with dyslipidemia. Many other herbs such as Amla [84,85] have also shown promising

results for controlling lipid parameters among patients with hyperlipidemia/dyslipidemia. However, these studies failed to meet the inclusion criteria of the current review.
